The objective of this project is to detect natural and induced mutations in mice for the purpose of providing understanding of the specific molecular events involved in germinal mutation and the effects of these events on the life, form and function of the mammalian organism. Results are relevant to cases of human exposures to mutagens and the potential for increased risk of genetic disease that may accompany mutagen exposure. The problem is approached by detecting mutations at specific biochemical loci with electrophoretic methods, by conducting characterization studies on the mutant genes and gene products, and by examining the animals for expressed physical abnormalities correlated with mutation rate increases and with specific induced-mutant genotypes. The methods have led to successful identification of more than 20 ethylnitrosourea-induced mutants affecting proteins such as malic enzyme, a alpha hemoglobin and phosphoglucomutase, but there is little evidence to suggest that most of the mutants are detrimental to health-related characteristics. The results raise questions as to the extent hypotheses of human genetic risk based upon increased mutation rates are indicative of elevated probabilities for significant genetic damage. As some mutagens are therapeutically beneficial the possibility of false risk estimates and unjustified restrictions on mutagen exposures raise important medical and legal considerations. Previously published mammalian-genetic data are being reexamined to determine if new interpretations are possible, and laboratory experiments involving the use of other mutagens and more powerful detection techniques are planned for the future.